Salmonella typhi (typhoid fever)

Salmonella is a bacterium belonging to the family Enterobacteriaceae.

There are two main species: Salmonella bongori and Salmonella enterica, which itself has six subspecies.

One of the subspecies is enterica, which has over 2500 serotypes that can be divided into two main groups based on the clinical symptoms they cause typhoidal or non-typhoidal Salmonella.

The typhoidal group, which includes serotype Salmonella typhi (S. typhi), specifically infects humans and causes enteric fever, which is more commonly called typhoid fever.

If left untreated, it can be fatal and throughout history, has been the cause of death of aviator and engineer Wilbur Wright, one of the Wright brothers; Dr. Hashimoto, the first to describe Hashimoto's thyroiditis; and several people in New York City infected by “Typhoid Mary” in the first documented asymptomatic carrier of the disease in the United States.

OK, but generally, Salmonella are encapsulated gram-negative, rod bacteria – meaning, they have a polysaccharide layer outside the cell envelope and look like little red or pink sticks on a gram stain.

They’re facultative intracellular pathogens, meaning they can live both outside or inside of its host’s cells.

And have flagella, making them motile, but don’t form spores.

They’re also facultative anaerobes, so they can undergo respiratory and fermentative metabolism; and they can ferment glucose but not lactose; are oxidase negative; and produce hydrogen sulfide gas.

And while a variety of media can be used to selectively identify Salmonella, among them is Triple Sugar Iron agar which produces a black precipitate when hydrogen sulfide is produced.

Now, once Salmonella is ingested and reaches the distal ileum of the small intestine, it targets the epithelial layer of the mucosal lining.

Here, it uses surface appendages to adhere to microfold cells, or M-cells. And these M-cells eat, or phagocytose, the bacteria from the intestinal lumen and spit it out into the underlying Peyer’s patches - a type of mucosal immune tissue that extends into the submucosa.

And, well, S. typhi has a Vi capsular polysaccharide antigen virulence factor, which helps protect the bacteria from being tagged with antibodies that signal leukocytes like neutrophils to come in and phagocytose the bacteria.

Moreover, neutrophil recruitment is also suppressed.

On the other hand, the recruitment of monocytes and macrophages is induced, making them the primary cells that respond to the infection.

And as they are recruited to the infection site, they cause hypertrophy and necrosis of the surrounding tissues; which can damage the epithelial lining, and potentially lead to ileal perforation, consequently, a secondary infection of the peritoneum.

Now, aside from that, macrophages also phagocytose S. typhi, so the bacteria is slowly engulfed by the cell membrane, which invaginates to form a sac on its inner side.

The sac then separates from the actual cell membrane forming what’s referred to a Salmonella-containing vacuoles.

Normally, the vacuole would fuse with the host cell’s lysosomes, which are organelles filled with digestive enzymes that destroy the bacteria.

But, S. typhi uses needle-like protein appendage, called a Type III secretion system, to inject a variety of effector proteins across the vacuole membrane and into the host cell’s cytoplasm.

This leads to a remodeling of the vacuole that prevents fusion with the lysosome, so S. typhi survives and replicates within the vacuole.

All the while, S. typhi is using the host macrophage to hitch a ride to the nearby lymphatic vessels that drain into local mesenteric lymph nodes.

Once there, the macrophage can continue to flow through the thoracic duct and into systemic lymphatic circulation where they can enter reticuloendothelial tissues in the liver, spleen, bone marrow, gall bladder and additional lymph nodes.

At about this point, S. typhi can induce macrophage apoptosis, or cell death, so the bacteria is released into the bloodstream, called bacteremia.

Bacteremia can progress to sepsis, an acutely life-threatening condition characterized by systemic vasodilation and hypoperfusion of vital organs - which means the organs aren’t getting enough nutrient and oxygen-rich blood.

Another complication can arise in individuals with spleen issues, because the spleen plays an important role in immunity against encapsulated bacteria.

This includes people who have undergone a splenectomy, or spleen removal, or those with sickle cell disease, who have functional asplenia.